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Published on: June 19, 2025
Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac
Nobuhiro Suematsu1, Hiroyuki Tsutsui, Jing Wen
1Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Background:
Tumor necrosis factor-alpha (TNF-alpha) and angiotensin II (Ang II) are implicated in the development and further progression of heart failure, which might be, at least in part, mediated by the production of reactive oxygen species (ROS). However, the cause and consequences of this agonist-mediated ROS production in cardiac myocytes have not been well defined. Recently, we demonstrated that increased ROS production was associated with mitochondrial DNA (mtDNA) damage and dysfunction in failing hearts. We thus investigated whether the direct exposure of cardiac myocytes to TNF-alpha and Ang II in vitro could induce mtDNA damage via production of ROS.
Methods And Results:
TNF-alpha increased ROS production within cultured neonatal rat ventricular myocytes after 1 hour, as assessed by 2',7'-dichlorofluorescin diacetate fluorescence microscopy. TNF-alpha also decreased mtDNA copy number by Southern blot analysis in association with complex III activity, which was prevented in the presence of the antioxidant alpha-tocopherol. A direct exposure of myocytes to H2O2 caused a similar decrease in mtDNA copy number. In contrast, Ang II did not affect mtDNA copy number, despite the similar increase in ROS production. TNF-alpha-mediated ROS production and a decrease in mtDNA copy number were inhibited by the sphingomyelinase inhibitor D609. Furthermore, N-acetylsphingosine (C2-ceramide), a synthetic cell-permeable ceramide analogue, increased myocyte ROS production, suggesting that TNF-alpha-mediated ROS production and subsequent mtDNA damage were mediated by the sphingomyelin-ceramide signaling pathway.
Conclusions:
The intimate link between TNF-alpha, ROS, and mtDNA damage might play an important role in myocardial remodeling and failure.
Insights
Tumor necrosis factor-alpha (TNF-alpha) triggers reactive oxygen species (ROS) production and mitochondrial DNA (mtDNA) damage in heart cells, contributing to heart failure. Angiotensin II (Ang II) increases ROS but does not damage mtDNA.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Tumor necrosis factor-alpha (TNF-alpha) and angiotensin II (Ang II) are linked to heart failure progression, potentially via reactive oxygen species (ROS).
- The precise mechanisms of agonist-induced ROS production and its impact on cardiac myocytes, particularly mitochondrial DNA (mtDNA), remain unclear.
- Previous studies indicated a correlation between elevated ROS, mtDNA damage, and dysfunction in failing hearts.
Purpose of the Study:
- To investigate if direct exposure of cardiac myocytes to TNF-alpha and Ang II in vitro induces mtDNA damage through ROS production.
- To elucidate the signaling pathways involved in TNF-alpha-mediated ROS production and subsequent mtDNA damage.
Main Methods:
- Cultured neonatal rat ventricular myocytes were exposed to TNF-alpha and Ang II.
- Reactive oxygen species (ROS) production was assessed using 2',7'-dichlorofluorescin diacetate fluorescence.
- Mitochondrial DNA (mtDNA) copy number was quantified by Southern blot analysis.
- The role of the sphingomyelin-ceramide pathway was examined using D609 and C2-ceramide.
Main Results:
- TNF-alpha significantly increased ROS production and decreased mtDNA copy number in myocytes.
- The TNF-alpha-induced decrease in mtDNA copy number was associated with reduced complex III activity and was prevented by alpha-tocopherol.
- Hydrogen peroxide (H2O2) exposure mimicked the mtDNA copy number reduction.
- Ang II increased ROS but did not affect mtDNA copy number.
- The sphingomyelinase inhibitor D609 and C2-ceramide blocked TNF-alpha-mediated ROS production and mtDNA damage, implicating the sphingomyelin-ceramide pathway.
Conclusions:
- TNF-alpha induces cardiac myocyte ROS production and mtDNA damage via the sphingomyelin-ceramide pathway.
- This link between TNF-alpha, ROS, and mtDNA damage is a potential contributor to myocardial remodeling and heart failure.
- Angiotensin II's role in mtDNA damage appears distinct from TNF-alpha despite similar ROS induction.
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